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Abstract:

Described herein are methods of treating Parkinson's disease using
arylcyclopropylamine compounds.

Claims:

1. A method of treating Parkinson's disease in a subject in need of
treatment, comprising administering to the subject an effective amount of
a compound of formula (I): ##STR00129## wherein R1, R2,
R3, R4 and R5 are independently selected from hydrogen,
C1-7 alkyl, C3-20 heterocyclyl, C5-20 aryl, C1-7
alkoxy, C1-7 haloalkyl, halo, amino, cyano, nitro, ether and
thioether, or any two of R1, R2, R3, R4 and R5
may be taken together with the carbon atoms to which they are attached to
form an optionally substituted ring; and R6 is selected from
hydrogen and optionally substituted C5-20 aryl; or an isomer,
prodrug or pharmaceutically acceptable salt thereof.

4. The method of claim 1, wherein R2 and R3 are taken together
with the carbon atoms to which they are attached to form a C3-20
heterocyclyl ring.

5. The method of claim 4, wherein R2 and R3 are taken together
to form a five-membered heterocyclyl ring.

6. The method of claim 1, wherein R6 is hydrogen.

7. The method of claim 1, wherein the compound of formula (I) is selected
from the group consisting of: ##STR00130## or a pharmaceutically
acceptable salt thereof.

8.-18. (canceled)

19. A method of treating Parkinson's disease in a subject in need of
treatment, comprising administering to the subject an effective amount of
a compound of formula (IX): ##STR00131## wherein: A is a
C5-C6 aryl, cycloalkenyl or heterocyclyl ring; or an isomer,
prodrug or pharmaceutically acceptable salt thereof.

20. The method of claim 19, wherein A is a heterocyclyl ring.

21. The method of claim 19, wherein A is a bicyclic heterocyclyl ring.

22. The method of claim 19, wherein the compound is of formula (X):
##STR00132## wherein X1 is selected from CH2, O, S, and NH;
and - - - represents the presence or absence of a bond.

23. The method of claim 19, wherein the compound is of formula (XI):
##STR00133## wherein X1 is selected from CH2, O, S, and NH;
and - - - represents the presence or absence of a bond.

24. The method of claim 19, wherein the compound is of formula (XII):
##STR00134## wherein X1 is selected from CH2, O, S, and NH; n
is 1 or 2; and - - - represents the presence or absence of a bond.

25. The method of claim 19, wherein the compound is of formula (XIII):
##STR00135## wherein X2, X3, X4 and X5 are
independently selected from CH and N.

26. The method of claim 19, wherein the compound is of formula (XIV):
##STR00136## wherein X1 and X2 are independently selected from
O and S; and n is 1 or 2.

27. The method of claim 26, wherein X1 and X2 are O.

28. The method of claim 26, wherein n is 1.

29.-39. (canceled)

40. A pharmaceutical composition comprising a compound having the
following formula: ##STR00137## or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier.

Description:

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent
Application No. 61/579,872, filed on Dec. 23, 2011, the entire contents
of which are hereby incorporated by reference.

BACKGROUND

[0003] Although there is no known cure for Parkinson's disease (PD), one
of the two most common neurodegenerative diseases of aging, dopamine (DA)
replacement therapy by administration of the DA biosynthetic precursor
levodopa (L-DOPA or LD) has been employed for over 40 years as the gold
standard for treatment of PD-associated symptoms. However, the efficacy
of this treatment may wane with time, and the drug may have a number of
long-term side-effects including L-DOPA-induced dyskinesias (LIDs),
fluctuations in motor performance, and hallucinations. Often these
effects can become dose limiting at a time when patients are in need of
more medication and not less. DA agonists, as well as several other
classes of drugs directly or indirectly affecting DA function (monoamine
oxidase (MAO) inhibitors, catechol-O-methyl transferase (COMT)
inhibitors, and amantadine), may have some beneficial effects in PD
patients, but none of these drugs are as effective as L-DOPA, and some,
such as the dopamine agonists, may also have burdensome side-effects. Due
to such limitations, effective anti-Parkinsonian agents that are free of
side-effects such as dyskinesia, and/or agents that ameliorate
dyskinesias are needed.

SUMMARY

[0004] In one aspect, the disclosure provides a method of treating
Parkinson's disease in a subject in need of treatment, comprising
administering to the subject an effective amount of a compound of formula
(I):

##STR00001##

[0005] wherein R1, R2, R3, R4 and R5 are
independently selected from hydrogen, C1-7 alkyl, C3-20
heterocyclyl, C5-20 aryl, C1-7 alkoxy, C1-7 haloalkyl,
halo, amino, cyano, nitro, ether and thioether, or any two of R1,
R2, R3, R4 and R5 may be taken together with the
carbon atoms to which they are attached to form an optionally substituted
ring; and

[0007] or an isomer, prodrug or pharmaceutically acceptable salt thereof.

[0008] In one aspect, the disclosure provides a method of treating
Parkinson's disease in a subject in need of treatment, comprising
administering to the subject an effective amount of a compound of formula
(II):

[0012] In another aspect, the disclosure provides a method of treating
Parkinson's disease in a subject in need of treatment, comprising
administering to the subject an effective amount of a compound of formula
(IX):

##STR00003##

[0013] wherein:

[0014] A is a C5-C6 aryl, cycloalkenyl or heterocyclyl ring.

[0015] In another aspect, the disclosure provides a method of treating
Parkinson's disease in a subject in need of treatment, comprising
administering to the subject an effective amount of a compound of formula
(XV):

[0017] In another aspect, the disclosure provides a method of treating
Parkinson's disease in a subject in need of treatment, comprising
administering to the subject an effective amount of a compound described
herein and L-3,4-dihydroxyphenylalanine (L-DOPA).

[0018] In another aspect, the disclosure provides a method of reducing
dyskinesia in a subject in need thereof, comprising administering to the
subject an effective amount of a compound described herein. In
embodiments, the dyskinesia may be an L-DOPA-induced dyskinesia.

[0019] In another aspect, the disclosure provides a a pharmaceutical
composition comprising a compound having the following formula:

##STR00005##

[0020] or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.

[0021] Other aspects and embodiments will become apparent in light of the
following disclosure and drawings.

[0025] FIG. 4 illustrates results of treatment of DDD mice (n=6 for each)
with phenylcyclopropylamines (5 mg/kg) and L-DOPA/Carpidopa (LD/CD, 10/10
mg/kg). A) Total distance after treatment with 3 and LD/CD. B) Vertical
activity after treatment with compound 3 and LD/CD. C) Total distance
after treatment with compound 4 and LD/CD. D) Vertical activity after
treatment with compound 4 and LD/CD. E) Total distance after treatment
with compound 5 and LD/CD. F) Vertical activity after treatment with
compound 5 and LD/CD. G) Total distance after treatment with compound 7
and LD/CD. H) Vertical activity after treatment with compound 7 and
LD/CD.

[0028] Before any embodiments of the disclosure are explained in detail,
it is to be understood that the methods of the disclosure are not limited
in application to the details of construction and the arrangement of
components set forth in the following description or illustrated in the
following drawings. The methods of the disclosure are capable of other
embodiments and of being practiced or of being carried out in various
ways. Also, it is to be understood that the phraseology and terminology
used herein is for the purpose of description and should not be regarded
as limiting. The use of "including," "comprising," or "having" and
variations thereof herein is meant to encompass the items listed
thereafter and equivalents thereof as well as additional items.

[0030] The term "C5-20 aryl", as used herein, pertains to a
monovalent moiety obtained by removing a hydrogen atom from an aromatic
ring atom of a C5-20 aromatic compound, said compound having one
ring, or two or more rings (e.g., fused), and having from 5 to 20 ring
atoms, and wherein at least one of said ring(s) is an aromatic ring.
Suitably, each ring has from 5 to 7 ring atoms.

[0031] The ring atoms may be all carbon atoms, as in "carboaryl groups",
in which case the group may conveniently be referred to as a "C5-20
carboaryl" group. Examples of C5-20 aryl groups which do not have
ring heteroatoms (i.e. C5-20 carboaryl groups) include, but are not
limited to, those derived from benzene (i.e. phenyl) (C6), naphthalene
(C10), anthracene (C14), phenanthrene (C14), naphthacene (C18), and
pyrene (C16).

[0032] Examples of aryl groups which comprise fused rings, one of which is
not an aromatic ring, include, but are not limited to, groups derived
from indene and fluorene.

[0033] Alternatively, the ring atoms may include one or more heteroatoms,
including but not limited to oxygen, nitrogen, and sulfur, as in
"heteroaryl groups". In this case, the group may conveniently be referred
to as a "C5-20 heteroaryl" group, wherein "C5-20" denotes ring
atoms, whether carbon atoms or heteroatoms. Suitably, each ring has from
5 to 7 ring atoms, of which from 0 to 4 are ring heteroatoms. Examples of
C5-20 heteroaryl groups include, but are not limited to, C5
heteroaryl groups derived from furan (oxole), thiophene (thiole), pyrrole
(azole), imidazole (1,3-diazole), pyrazole (1,2-diazole), triazole,
oxazole, isoxazole, thiazole, isothiazole, oxadiazole, tetrazole,
oxadiazole (furazan) and oxatriazole; and C6 heteroaryl groups derived
from isoxazine, pyridine (azine), pyridazine (1,2-diazine), pyrimidine
(1,3-diazine; e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine)
and triazine.

[0034] The above C5-20 aryl groups whether alone or part of another
substituent, may themselves optionally be substituted with one or more
groups selected from themselves and the additional substituents listed
below.

[0035] The term "C1-7 alkyl", as used herein, pertains to a
monovalent moiety obtained by removing a hydrogen atom from a hydrocarbon
compound having from 1 to 7 carbon atoms, which may be aliphatic or
alicyclic, or a combination thereof, and which may be saturated,
partially unsaturated, or fully unsaturated. Suitably, the alkyl group
contains from 3 to 7 carbon atoms, i.e. is a "C3-7 alkyl".

[0038] Examples of saturated alicyclic C1-7 alkyl groups (also
referred to as "C3-7 cycloalkyl" groups) include, but are not
limited to, groups such as cyclopropyl, cyclobutyl, cyclopentyl, and
cyclohexyl, as well as substituted groups (e.g., groups which comprise
such groups), such as methylcyclopropyl, dimethylcyclopropyl,
methylcyclobutyl, dimethylcyclobutyl, methylcyclopentyl,
dimethylcyclopentyl, methylcyclohexyl, dimethylcyclohexyl,
cyclopropylmethyl and cyclohexylmethyl.

[0039] Examples of unsaturated C1-7 alkyl groups which have one or
more carbon-carbon double bonds (also referred to as "C2-7 alkenyl"
groups) include, but are not limited to, ethenyl (vinyl,
--CH═CH2), 2-propenyl (allyl, --CH--CH═CH2),
isopropenyl (--C(CH3)═CH2), butenyl, pentenyl, and hexenyl.

[0040] Examples of unsaturated C1-7 alkyl groups which have one or
more carbon-carbon triple bonds (also referred to as "C2-7 alkynyl"
groups) include, but are not limited to, ethynyl and 2-propynyl
(propargyl).

[0041] Examples of unsaturated alicyclic (carbocyclic) C1-7 alkyl
groups which have one or more carbon-carbon double bonds (also referred
to as "C3-7 cycloalkenyl" groups) include, but are not limited to,
unsubstituted groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl,
and cyclohexenyl, as well as substituted groups (e.g., groups which
comprise such groups) such as cyclopropenylmethyl and cyclohexenylmethyl.

[0042] The term "C3-20 heterocyclyl", as used herein, pertains to a
monovalent moiety obtained by removing a hydrogen atom from a ring atom
of a C3-20 heterocyclic compound, said compound having one ring, or
two or more rings (e.g., spiro, fused, bridged), and having from 3 to 20
ring atoms, of which from 1 to 10 are ring heteroatoms, and wherein at
least one of said ring(s) is a heterocyclic ring. Suitably, each ring has
from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms. Ring
heteroatoms may be selected from the group consisting of O, N, S and P.
"C3-20" denotes ring atoms, whether carbon atoms or heteroatoms.

[0045] Examples of C3-20 heterocyclyl groups having one sulfur ring
atom include, but are not limited to, those derived from thiirane,
thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran),
and thiepane.

[0046] Examples of C3-20 heterocyclyl groups having two oxygen ring
atoms include, but are not limited to, those derived from dioxolane,
dioxane, and dioxepane.

[0047] Examples of C3-20 heterocyclyl groups having two nitrogen ring
atoms include, but are not limited to, those derived from imidazolidine,
pyrazolidine (diazolidine), imidazoline, pyrazoline (dihydropyrazole),
and piperazine.

[0048] Examples of C3-20 heterocyclyl groups having one nitrogen ring
atom and one oxygen ring atom include, but are not limited to, those
derived from tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole,
dihydroisoxazole, morpholine, tetrahydrooxazine, dihydrooxazine, and
oxazine.

[0049] Examples of C3-20 heterocyclyl groups having one oxygen ring
atom and one sulfur ring atom include, but are not limited to, those
derived from oxathiolane and oxathiane (thioxane).

[0050] Examples of C3-20 heterocyclyl groups having one nitrogen ring
atom and one sulfur ring atom include, but are not limited to, those
derived from thiazoline, thiazolidine, and thiomorpholine.

[0052] Other examples of C3-20 heterocyclyl groups include, but are
not limited to, oxadiazine and oxathiazine.

[0053] Examples of heterocyclyl groups which additionally bear one or more
oxo (═O) groups, include, but are not limited to, those derived from:
C5 heterocyclics, such as furanone, pyrone, pyrrolidone (pyrrolidinone),
pyrazolone (pyrazolinone), imidazolidone, thiazolone, and isothiazolone;
C6 heterocyclics, such as piperidinone (piperidone), piperidinedione,
piperazinone, piperazinedione, pyridazinone, and pyrimidinone (e.g.,
cytosine, thymine, uracil), and barbituric acid; fused heterocyclics,
such as oxindole, purinone (e.g., guanine), benzoxazolinone, benzopyrone
(e.g., coumarin); cyclic anhydrides (--C(═O)--O--C(═O)-- in a
ring), including but not limited to maleic anhydride, succinic anhydride,
and glutaric anhydride; cyclic carbonates (--O--C(═O)--O-- in a
ring), such as ethylene carbonate and 1,2-propylene carbonate; imides
(--C(═O)--NR--C(═O)-- in a ring), including but not limited to,
succinimide, maleimide, phthalimide, and glutarimide; lactones (cyclic
esters, --O--C(═O)-- in a ring), including, but not limited to,
β-propiolactone, γ-butyrolactone, δ-valerolactone
(2-piperidone), and ε-caprolactone; lactams (cyclic amides,
--NR--C(═O)-- in a ring), including, but not limited to,
β-propiolactam, γ-butyrolactam (2-pyrrolidone),
δ-valerolactam, and ε-caprolactam; cyclic carbamates
(--O--C(═O)--NR-- in a ring), such as 2-oxazolidone; cyclic ureas
(--NR--C(═O)--NR-- in a ring), such as 2-imidazolidone and
pyrimidine-2,4-dione (e.g., thymine, uracil).

[0054] Halo: --F, --Cl, --Br, and --I.

[0055] Hydroxy: --OH.

[0056] Ether: --OR, wherein R is an ether substituent, for example, a
C1-7 alkyl group (also referred to as a C1-7 alkoxy group,
discussed below), a C3-20 heterocyclyl group (also referred to as a
C3-20 heterocyclyloxy group), a C5-20 aryl group (also referred
to as a C5-20 aryloxy group), or a C5-20 arylalkyl group (also
referred to as a C5-20 arylalkyloxy group), for example, a benzyl
group.

[0058] Oxo (keto, -one): ═O. Examples of cyclic compounds and/or
groups having, as a substituent, an oxo group (═O) include, but are
not limited to, carbocyclics such as cyclopentanone and cyclohexanone;
heterocyclics, such as pyrone, pyrrolidone, pyrazolone, pyrazolinone,
piperidone, piperidinedione, piperazinedione, and imidazolidone; cyclic
anhydrides, including but not limited to maleic anhydride and succinic
anhydride; cyclic carbonates, such as propylene carbonate; imides,
including but not limited to, succinimide and maleimide; lactones (cyclic
esters, --O--C(═O)-- in a ring), including, but not limited to,
β-propiolactone, γ-butyrolactone, δ-valerolactone, and
ε-caprolactone; and lactams (cyclic amides, --NH--C(═O)-- in
a ring), including, but not limited to, β-propiolactam,
γ-butyrolactam (2-pyrrolidone), δ-valerolactam, and
ε-caprolactam.

[0061] Acyl (keto): --C(═O)R, wherein R is an acyl substituent, for
example, a C1-7 alkyl group (also referred to as C1-7 alkylacyl
or C1-7 alkanoyl), a C3-20 heterocyclyl group (also referred to
as C3-20 heterocyclylacyl), or a C5-20 aryl group (also
referred to as C5-20 arylacyl). Examples of acyl groups include, but
are not limited to, --C(═O)CH3 (acetyl),
--C(═O)CH2CH3 (propionyl), --C(═O)C(CH3)3
(butyryl), and --C(═O)Ph (benzoyl, phenone).

[0065] Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide):
--C(═O)NR1R2, wherein R1 and R2 are independently amino substituents,
as defined for amino groups. Examples of amido groups include, but are
not limited to, --C(═O)NH2, --C(═O)NHCH3,
--C(═O)N(CH3)2, --C(═O)NHCH2CH3, and
--C(═O)N(CH2CH3)2, as well as amido groups in which R1
and R2, together with the nitrogen atom to which they are attached, form
a heterocyclic structure as in, for example, piperidinocarbonyl,
morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl.

[0066] Acylamido (acylamino): --NR1C(═O)R2, wherein R1 is an amide
substituent, for example, hydrogen, a C1-7 alkyl group, a C3-20
heterocyclyl group, or a C5-20 aryl group, and R2 is an acyl
substituent, for example, a C1-7 alkyl group, a C3-20
heterocyclyl group, or a C5-20 aryl group. Examples of acylamide
groups include, but are not limited to, --NHC(═O)CH3,
--NHC(═O)CH2CH3, and --NHC(═O)Ph. R1 and R2 may
together form a cyclic structure, as in, for example, succinimidyl,
maleimidyl and phthalimidyl.

[0068] Carbamate: --NR1-C(O)--OR2 wherein R1 is an amino substituent as
defined for amino groups and R2 is an ester group as defined for ester
groups. Examples of carbamate groups include, but are not limited to,
--NH--C(O)--O-Me, --NMe-C(O)--O-Me, --NH--C(O)--O-Et,
--NMe-C(O)--O-t-butyl, and --NH--C(O)--O-Ph.

[0070] Tetrazolyl: a five membered aromatic ring having four nitrogen
atoms and one carbon atom.

[0071] Amino: --NR1R2, wherein R1 and R2 are independently amino
substituents, for example, hydrogen, a C1-7 alkyl group (also
referred to as C1-7 alkylamino or di-C1-7 alkylamino), a
C3-20 heterocyclyl group, or a C5-20 aryl group, or, in the
case of a "cyclic" amino group, R1 and R2, taken together with the
nitrogen atom to which they are attached, form a heterocyclic ring having
from 4 to 8 ring atoms. Examples of amino groups include, but are not
limited to, --NH2, --NHCH3, --NHC(CH3)2,
--N(CH3)2, --N(CH2CH3)2, and --NHPh. Examples of
cyclic amino groups include, but are not limited to, aziridino,
azetidino, pyrrolidino, piperidino, piperazino, morpholino, and
thiomorpholino.

[0073] Amidine: --C(═NR)NR2, wherein each R is an amidine
substituent, for example, hydrogen, a C1-7 alkyl group, a C3-20
heterocyclyl group, or a C5-20 aryl group. An example of an amidine
group is --C(═NH)NH2.

[0085] Thioether (sulfide): --SR, wherein R is a thioether substituent,
for example, a C1-7 alkyl group (also referred to as a C1-7
alkylthio group), a C3-20 heterocyclyl group, or a C5-20 aryl
group. Examples of C1-7 alkylthio groups include, but are not
limited to, --SCH3 and --SCH2CH3.

[0086] Disulfide: --SS--R, wherein R is a disulfide substituent, for
example, a C1-7 alkyl group (also referred to herein as C1-7
alkyl disulfide), a C3-20 heterocyclyl group, or a C5-20 aryl
group. Examples of C1-7 alkyl disulfide groups include, but are not
limited to, --SSCH3 and --SSCH2CH3.

[0088] Sulfine (sulfinyl, sulfoxide): --S(═O)R, wherein R is a sulfine
substituent, for example, a C1-7 alkyl group, a C3-20
heterocyclyl group, or a C5-20 aryl group. Examples of sulfine
groups include, but are not limited to, --S(═O)CH3 and
--S(═O)CH2CH3.

[0089] Sulfonyloxy: --OS(═O)2R, wherein R is a sulfonyloxy
substituent, for example, a C1-7 alkyl group, a C3-20
heterocyclyl group, or a C5-20 aryl group. Examples of sulfonyloxy
groups include, but are not limited to, --OS(═O)2CH3 and
--OS(═O)2CH2CH3.

[0090] Sulfinyloxy: --OS(═O)R, wherein R is a sulfinyloxy substituent,
for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or
a C5-20 aryl group. Examples of sulfinyloxy groups include, but are
not limited to, --OS(═O)CH3 and --OS(═O)CH2CH3.

[0091] Sulfamino: --NR1S(═O)2OH, wherein R1 is an amino
substituent, as defined for amino groups. Examples of sulfamino groups
include, but are not limited to, --NHS(═O)2OH and
--N(CH3)S(═O)2OH.

[0092] Sulfinamino: --NR1S(═O)R, wherein R1 is an amino substituent,
as defined for amino groups, and R is a sulfinamino substituent, for
example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a
C5-20 aryl group. Examples of sulfinamino groups include, but are
not limited to, --NHS(═O)CH3 and
--N(CH3)S(═O)C6H5.

[0094] Sulfonamino: --NR1S(═O)2R, wherein R1 is an amino
substituent, as defined for amino groups, and R is a sulfonamino
substituent, for example, a C1-7 alkyl group, a C3-20
heterocyclyl group, or a C5-20 aryl group. Examples of sulfonamino
groups include, but are not limited to, --NHS(═O)2CH3 and
--N(CH3)S(═O)2C6H5.

[0095] Phosphoramidite: --OP(OR1)-N(R2)2, where R1 and R2 are
phosphoramidite substituents, for example, --H, a C1-7 alkyl group,
a C3-20 heterocyclyl group, or a C5-20 aryl group. Examples of
phosphoramidite groups include, but are not limited to,
--OP(OCH2CH3)--N(CH3)2,
--OP(OCH2CH3)--N(i-Pr)2, and
--OP(OCH2CH2CN)--N(i-Pr)2.

[0096] Phosphoramidate: --OP(═O)(OR1)-N(R2)2, where R1 and R2 are
phosphoramidate substituents, for example, --H, a C1-7 alkyl group,
a C3-20 heterocyclyl group, or a C5-20 aryl group. Examples of
phosphoramidate groups include, but are not limited to,
--OP(═O)(OCH2CH3)--N(CH3)2,
--OP(═O)(OCH2CH3)--N(i-Pr)2, and
--OP(═O)(OCH2CH2CN)--N(i-Pr)2.

[0097] In many cases, substituents may themselves be substituted. For
example, a C1-7 alkoxy group may be substituted with, for example, a
C1-7 alkyl (also referred to as a C1-7 alkyl-C1-7 alkoxy
group), for example, cyclohexylmethoxy, a C3-20 heterocyclyl group
(also referred to as a C5-20 heterocyclyl-C1-7 alkoxy group),
for example phthalimidoethoxy, or a C5-20 aryl group (also referred
to as a C5-20 aryl-C1-7 alkoxy group), for example, benzyloxy.

Compounds

[0098] Compounds that may be used in the methods described herein include
compounds of formula (I):

##STR00006##

[0099] wherein R1, R2, R3, R4 and R5 are
independently selected from hydrogen, C1-7 alkyl, C3-20
heterocyclyl, C5-20 aryl, C1-7 alkoxy, C1-7 haloalkyl,
halo, amino, cyano, nitro, ether and thioether, or any two of R1,
R2, R3, R4 and R5 may be taken together with the
carbon atoms to which they are attached to form an optionally substituted
ring; and

[0103] In some embodiments, R3 is halo (e.g., bromo). In some
embodiments, R3 is haloalkyl (e.g., trifluoromethyl). In some
embodiments, R3 is C1-7 alkoxy (e.g., methoxy, ethoxy or
isopropoxy). In some embodiments, R3 is ether (e.g., --O-aryl such
as --O-phenyl).

[0104] Compounds that may be used in the methods described herein include
compounds of formula (II):

[0133] In some embodiments, R13 is C2-7 alkoxy, such as ethoxy
or isopropoxy. In some embodiments, R13 is ether, such as phenoxy or
benzyloxy. In some embodiments, R13 is amino. In some embodiments,
R13 is thioether.

[0134] In embodiments, compounds that may be used in the methods described
herein include compounds of formula (XVI):

##STR00022##

[0135] where A is an optionally substituted C5-20 aryl group, or an
isomer, prodrug or pharmaceutically acceptable salt thereof.

[0136] Suitable compounds include:

##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027##

[0137] Suitable compounds include those described in U.S. Patent
Publication No. 2010/0324147, and in Gooden et al., Bioorg. Med. Chem.
Lett. 18 (2008) 3047-3051, each of which is incorporated herein by
reference in its entirety.

[0139] Note that, except as discussed below for tautomeric forms,
specifically excluded from the term "isomers", as used herein, are
structural (or constitutional) isomers (i.e. isomers which differ in the
connections between atoms rather than merely by the position of atoms in
space). For example, a reference to a methoxy group, --OCH3, is not
to be construed as a reference to its structural isomer, a hydroxymethyl
group, --CH2OH. Similarly, a reference to ortho-chlorophenyl is not
to be construed as a reference to its structural isomer, meta
chlorophenyl. However, a reference to a class of structures may well
include structurally isomeric forms falling within that class (e.g.,
C1-7 alkyl includes n-propyl and iso-propyl; butyl includes n-,
iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and
paramethoxyphenyl).

[0140] Note that specifically included in the term "isomer" are compounds
with one or more isotopic substitutions. For example, H may be in any
isotopic form, including 1H, 2H (D), and 3H (T); C may be
in any isotopic form, including 12C, 13C, and 14C; O may
be in any isotopic form, including 16O and 18O; and the like.

[0141] Unless otherwise specified, a reference to a particular compound
includes all such isomeric forms, including (wholly or partially) racemic
and other mixtures thereof. Methods for the preparation (e.g. asymmetric
synthesis) and separation (e.g., fractional crystallisation and
chromatographic means) of such isomeric forms are either known in the art
or are readily obtained by adapting the methods taught herein, or known
methods, in a known manner.

[0142] Unless otherwise specified, a reference to a particular compound
also includes ionic, salt, solvate, and protected forms of thereof, for
example, as discussed below. It may be convenient or desirable to
prepare, purify, and/or handle a corresponding salt of the active
compound, for example, a pharmaceutically-acceptable salt. Examples of
pharmaceutically acceptable salts are discussed in Berge et al., J.
Pharm. Sci., 66, 1-19 (1977). Exemplary pharmaceutically acceptable salts
include hydrochloride salts.

[0143] For example, if the compound is anionic, or has a functional group
which may be anionic (e.g., --COOH may be --COO--), then a salt may be
formed with a suitable cation. Examples of suitable inorganic cations
include, but are not limited to, alkali metal ions such as Na.sup.+ and
K.sup.+, alkaline earth cations such as Ca2+ and Mg2+, and
other cations such as Al3+. Examples of suitable organic cations
include, but are not limited to, ammonium ion (i.e., NH4+) and
substituted ammonium ions (e.g., NH3R.sup.+, NH2R2.sup.+,
NHR3.sup.+, NR4.sup.+). Examples of some suitable substituted
ammonium ions are those derived from: ethylamine, diethylamine,
dicyclohexylamine, triethylamine, butylamine, ethylenediamine,
ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine,
choline, meglumine, and tromethamine, as well as amino acids, such as
lysine and arginine. An example of a common quaternary ammonium ion is
N(CH3)4.sup.+.

[0144] If the compound is cationic, or has a functional group which may be
cationic (e.g., --NH2 may be --NH3.sup.+), then a salt may be
formed with a suitable anion. Examples of suitable inorganic anions
include, but are not limited to, those derived from the following
inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric,
sulfurous, nitric, nitrous, phosphoric, and phosphorous. Examples of
suitable organic anions include, but are not limited to, those derived
from the following organic acids: acetic, propionic, succinic, glycolic,
stearic, palmitic, lactic, malic, pamoic, tartaric, citric, gluconic,
ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, aspartic,
benzoic, cinnamic, pyruvic, salicyclic, sulfanilic, 2-acetyoxybenzoic,
fumaric, phenylsulfonic, toluenesulfonic, methanesulfonic,
ethanesulfonic, ethane disulfonic, oxalic, pantothenic, isethionic,
valeric, lactobionic, and gluconic. Examples of suitable polymeric anions
include, but are not limited to, those derived from the following
polymeric acids: tannic acid, carboxymethyl cellulose.

[0145] It may be convenient or desirable to prepare, purify, and/or handle
a corresponding solvate of the active compound. The term "solvate" is
used herein in the conventional sense to refer to a complex of solute
(e.g. active compound, salt of active compound) and solvent. If the
solvent is water, the solvate may be conveniently referred to as a
hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

[0146] It may be convenient or desirable to prepare, purify, and/or handle
the active compound in a chemically protected form. The term "chemically
protected form", as used herein, pertains to a compound in which one or
more reactive functional groups are protected from undesirable chemical
reactions, that is, are in the form of a protected or protecting group
(also known as a masked or masking group or a blocked or blocking group).
By protecting a reactive functional group, reactions involving other
unprotected reactive functional groups can be performed, without
affecting the protected group; the protecting group may be removed,
usually in a subsequent step, without substantially affecting the
remainder of the molecule. See, for example, Protective Groups in Organic
Synthesis (T. Green and P. Wuts, Wiley, 1999).

[0147] For example, a hydroxy group may be protected as an ether (--OR) or
an ester (--OC(═O)R), for example, as: a t-butyl ether; a benzyl,
benzhydryl (diphenylmethyl), or trityl (triphenylmethyl)ether; a
trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester
(--OC(═O)CH3, --OAc). For example, an aldehyde or ketone group
may be protected as an acetal or ketal, respectively, in which the
carbonyl group (>C═O) is converted to a diether (>C(OR)2),
by reaction with, for example, a primary alcohol. The aldehyde or ketone
group is readily regenerated by hydrolysis using a large excess of water
in the presence of acid. For example, an amine group may be protected,
for example, as an amide or a urethane, for example, as: a methyl amide
(--NHCO--CH3); a benzyloxy amide (--NHCO--OCH2C6H5,
--NHCbz); as a t-butoxy amide (--NHCO--OC(CH3)3, --NH-Boc); a
2-biphenyl-2-propoxy amide
(--NHCO--OC(CH3)2C6H4C6H5, --NH-Bpoc), as a
9-fluorenylmethoxy amide (--NH-Fmoc), as a 6-nitroveratryloxy amide
(--NH-Nvoc), as a 2-trimethylsilylethyloxy amide (--NH-Teoc), as a
2,2,2-trichloroethyloxy amide (--NH-Troc), as an allyloxy amide
(--NH-Alloc), as a 2(-phenylsulphonyl)ethyloxy amide (--NH-Psec); or, in
suitable cases, as an N-oxide.

[0148] For example, a carboxylic acid group may be protected as an ester
for example, as: an C1-7 alkyl ester (e.g. a methyl ester; a t-butyl
ester); a C1-7 haloalkyl ester (e.g., a C1-7
trihaloalkylester); a triC1-7 alkylsilyl-C1-7 alkyl ester; or a
C5-20 aryl-C1-7 alkyl ester (e.g. a benzyl ester; a nitrobenzyl
ester); or as an amide, for example, as a methyl amide.

[0149] For example, a thiol group may be protected as a thioether (--SR),
for example, as: a benzyl thioether; an acetamidomethyl ether
(--S--CH2NHC(═O)CH3). It may be convenient or desirable to
prepare, purify, and/or handle the active compound in the form of a
prodrug.

[0150] The term "prodrug", as used herein, pertains to a compound which,
when metabolized (e.g. in vivo), yields the desired active compound.
Typically, the prodrug is inactive, or less active than the active
compound, but may provide advantageous handling, administration, or
metabolic properties.

[0151] For example, some prodrugs are esters of the active compound (e.g.
a physiologically acceptable metabolically labile ester). During
metabolism, the ester group (--C(═O)OR) is cleaved to yield the
active drug. Such esters may be formed by esterification, for example, of
any of the carboxylic acid groups (--C(═O)OH) in the parent compound,
with, where appropriate, prior protection of any other reactive groups
present in the parent compound, followed by deprotection if required.
Examples of such metabolically labile esters include those wherein R is
C1-7 alkyl (e.g. -Me, -Et); C1-7 aminoalkyl (e.g. aminoethyl;
2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C1-7
alkyl (e.g. acyloxymethyl; acyloxyethyl; e.g. pivaloyloxymethyl;
acetoxymethyl; 1-acetoxyethyl;
1-(1-methoxy-1-methyl)ethyl-carbonxyloxyethyl; 1-(benzoyloxy)ethyl;
isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl;
cyclohexyl-carbonyloxymethyl; 1-cyclohexylcarbonyloxyethyl;
cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl;
(4-tetrahydropyranyloxy) carbonyloxymethyl;
1-(4-tetrahydropyranyloxy)carbonyloxyethyl;
(4-tetrahydropyranyl)carbonyloxymethyl; and
1-(4-tetrahydropyranyl)carbonyloxyethyl).

[0152] Also, some prodrugs are activated enzymatically to yield the active
compound, or a compound which, upon further chemical reaction, yields the
active compound. For example, the prodrug may be a sugar derivative or
other glycoside conjugate, or may be an amino acid ester derivative.

Synthesis of Compounds

[0153] Compounds of the invention may be synthesized according to Scheme
1. For example, an α,β-unsaturated carboxylic acid may be
protecting with an acid protecting group (e.g., as an ester such as a
methyl ester). Cyclopropanation may be effected by a number of methods,
such as use of the Corey-Chaykovsky reagent, or diazomethane in the
presence of a catalyst (e.g., palladium(II) acetate). Subsequent
deprotection (e.g., via hydrolysis) may be followed by conversion of the
carboxylic acid to a primary amine, e.g., via Curtius rearrangement or a
Hofmann rearrangement.

##STR00028##

[0154] The starting material may be a commercially available
α,β-unsaturated acid. Alternatively, an appropriate alkene may
be generated from the corresponding aryl aldehyde via an olefination
reaction (e.g., the Horner-Wadsworth-Emmons reaction). Additional
non-commerically available substituted benzaldehydes for olefination can
be prepared using a cross-coupling reaction (e.g., a copper-catalyzed
Ullmann coupling) between para-halobenzaldehydes and a variety of phenols
and thiophenols, as illustrated in Scheme 2.

##STR00029##

[0155] As can be appreciated by the skilled artisan, further methods of
synthesizing the compounds of the formulae herein will be evident to
those of ordinary skill in the art. Additionally, the various synthetic
steps may be performed in an alternate sequence or order to give the
desired compounds. Synthetic chemistry transformations and protecting
group methodologies (protection and deprotection) useful in synthesizing
the compounds described herein are known in the art and include, for
example, those such as described in R. Larock, Comprehensive Organic
Transformations, VCR Publishers (1989); T. W. Greene and P. G. M. Wuts,
Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons
(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic
Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia
of Reagents for Organic Synthesis, John Wiley and Sons (1995), and
subsequent editions thereof.

Evaluating Compounds

[0156] A variety of methods can be used to evaluate a compound for its
potential use in treatment of Parkinson's disease. Evaluation methods
include in vitro assays, in vitro cell-based assays, ex vivo assays and
in vivo methods. The methods can evaluate binding to a protein or enzyme,
an activity downstream of a protein or enzyme of interest, or treatment
or alleviation of symptoms.

[0158] This model has demonstrated that L-DOPA alone or given along with
carbidopa (CD) fully restored locomotion in DDD mice. These treatments
temporarily restored locomotion essentially up to the levels normally
observed in intact DAT-KO mice. Similarly, the non-selective D1/D2 DA
agonists apomorphine and pergolide were effective in treating akinesia,
as well as combined administration of the D1 and D2 agonists SKF81297
plus quinpirole, supporting cooperative interaction of D1/D2 DA receptors
in locomotor activity (Sotnikova et al. PLoS Biol., 2010, 5, p. e13452).
Accordingly, DDD mice may be very useful models of PD. Compounds
described herein may thus be evaluated using this model for their
abilities to restore locomotion in DDD mice.

[0159] Compounds described herein may also be evaluated in other widely
accepted animal models of Parkinson's disease. For example, compounds may
be evaluated in rats that have been treated with 6-hydroxydopamine
(6-OHDA). See Heidenreich et al. (2004) Exp Neurol 186:145-157;
Heidenreich et al. (1995) J Pharmacol Exp Ther 273:516-525; Turner et al.
(2008) Brain Struct Funct 213:197-213; and Turner et al. (2002) J
Pharmacol Exp Ther 301:371-381. Compounds may also be evaluated in
squirrel monkeys made Parkinsonian by injections of MPTP. This is a
validated model of PD that is well established at the Parkinson's
Institute. Animals may be drawn from a cohort of MPTP-lesioned animals
that have shown stable Parkinsonism scores over a period of more than 8
months. MPTP-treated squirrel monkeys offer a faithful model of PD
including a therapeutic response to LD/CD treatment that produces
significant reductions in Parkinsonian motor deficits in these animals.
Importantly, MPTP-lesioned animals given LD/CD also develop abnormal
involuntary movements (dyskinesias) that are quantifiable and nearly
identical to those observed in LD treated patients (Langston et al. Ann
Neurol 47, S79-89 (2000); Quik et al. Ann Neurol 62, 588-96 (2007); Hsu
et al. J Pharmacol Exp Ther 311, 770-7 (2004); Togasaki et al. Ann Neurol
50, 254-7 (2001); Togasaki et al. Neuropharmacology 48, 398-405 (2005)).

Treatment of Parkinson's Disease

[0160] Parkinson's disease (PD) is a debilitating neurological illness
that affects an estimated 6 million people worldwide; in 2007, it was the
14th leading cause of death in the United States. PD is largely
characterized by the irreversible loss of brain dopamine (DA) neurons. DA
neurotransmission is essential for normal locomotor functions and, in
most cases, PD becomes clinically apparent when the loss of dopaminergic
neurons reaches 60-70% leading to functional dysregulation of the related
neuronal circuitry. Major motor and non-motor manifestations of DA
deficiency in PD include tremors, rigidity, bradykinesia, cardiovascular
and gastrointestinal abnormalities, cognitive dysfunction, and
depression.

[0161] Currently, there is no known cure for PD. However, the symptoms can
be controlled by therapeutic interventions. DA replacement therapy is the
major medical approach to treating PD, and a variety of dopaminergic
agents are available. The most powerful drug is the immediate precursor
to dopamine, levodopa (L-DOPA). Although L-DOPA is the most effective
drug to treat the symptoms of PD, after five years or less of treatment
about 60% of patients develop complications including fluctuations in
motor performance as well as psychotic reactions and dyskinesia. DA
agonists, as well as several other classes directly or indirectly
affecting DA function (monoamine oxidase (MAO) inhibitors and
catechol-O-methyl transferase (COMT) inhibitors) have proven advantageous
in PD patients but are typically effective only when administered at
early stages of the disease or as supplementary medications to enhance
the benefits of L-DOPA.

[0162] In an aspect, the disclosure provides a method of treating
Parkinson's disease in a subject in need of treatment, comprising
administering to the subject an effective amount of a compound of any of
formulae (I)-(XVI) as described herein.

[0163] In another aspect, the disclosure provides a method of treating
Parkinson's disease in a subject in need of treatment, comprising
administering to the subject an effective amount of a compound of any of
formulae (I)-(XVI) as described herein, and L-3,4-dihydroxyphenylalanine
(L-DOPA).

[0164] In a further aspect, the disclosure provides a method of treating
or reducing dyskinesia in a subject in need thereof, comprising
administering to the subject an effective amount of a compound of any of
formulae (I)-(XVI) as described herein.

[0165] In yet a further aspect, the disclosure provides a method of
treating or reducing dyskinesia in a subject in need thereof, comprising
administering to the subject an effective amount of a compound of any of
formulae (I)-(XVI) as described herein, wherein the dyskinesia is induced
by, or associated with, L-3,4-dihydroxyphenylalanine (L-DOPA).

[0166] As used herein, "dyskinesia" relates to a movement disorder which
is typically characterized or indicated by involuntary, repetitive body
movements, along with diminished voluntary movement. Dyskinesia can
manifest itself broadly, from a slight tremor of the mouth or hands to
uncontrollable movement of the upper (commonly) or lower body. Dyskinesia
can be a symptom of any of several medical disorders and is distinguished
by the underlying cause. Chronic (or tardive) is a late onset dyskinesia,
which typically occurs after treatment with antipsychotic drugs (e.g.,
haloperidol or amoxapine). Common symptoms include tremors and writhing
movements of the body and limbs and, less frequently, movement in the
face and mouth. It may also involve involuntary lip smacking, repetitive
pouting of the lips and tongue protrusions.

[0167] In some embodiments, the methods disclosed herein relate to
treating or reducing dyskinesia that is associated with the movement
disorder commonly observed in patients with Parkinson's disease, also
referred to as Levodopa-induced dyskinesia (LID). This form of dyskinesia
commonly manifests itself in the form of jerky, dance-like movements of
the arms and/or head, and usually presents after several years of
treatment with L-DOPA (Levodopa).

[0168] The term "effective amount" as used herein, pertains to that amount
of an active compound, or a material, composition or dosage from
comprising an active compound, which produces some desired effect, such
as alleviation of symptoms or alleviation of side effects.

[0169] The term "treatment", as used herein in the context of treating a
condition, pertains generally to treatment and therapy, whether of a
human or an animal (e.g. in veterinary applications), in which a desired
therapeutic effect is achieved. For example, treatment may ameliorate the
condition or may inhibit the progress of the condition (e.g., reduce the
rate of progress or halt the rate of progress), or may alleviate symptoms
of the condition, or may alleviate side-effects of treatment with other
agents (e.g., dyskinesia).

[0170] The term "therapeutically-effective amount" as used herein,
pertains to that amount of an active compound, or a material, composition
or dosage form comprising an active compound, which is effective for
producing some desired therapeutic effect, commensurate with a reasonable
benefit/risk ratio.

Administration

[0171] The active compound or pharmaceutical composition comprising the
active compound may be administered to a subject by any convenient route
of administration, whether systemically/peripherally or at the site of
desired action, including but not limited to, oral (e.g. by ingestion);
topical (including e.g. transdermal, intranasal, ocular, buccal, and
sublingual); pulmonary (e.g. by inhalation or insufflation therapy using,
e.g. an aerosol, e.g. through mouth or nose); rectal; vaginal;
parenteral, for example, by injection, including subcutaneous,
intradermal, intramuscular, intravenous, intraarterial, intracardiac,
intrathecal, intraspinal, intracapsular, subcapsular, intraorbital,
intraperitoneal, intratracheal, subcuticular, intraarticular,
subarachnoid, and intrasternal; by implant of a depot, for example,
subcutaneously or intramuscularly.

[0172] In some embodiments, co-administration of an effective amount of a
compound of any of formulae (I)-(XVI) and L-3,4-dihydroxyphenylalanine
(L-DOPA) may be used in combination and optionally with other known PD
therapies. Administered "in combination," as used herein, means that two
(or more) different treatments are delivered to the subject during the
course of the subject's affliction with the disorder, e.g., the two or
more treatments are delivered after the subject has been diagnosed with
the disorder and before the disorder has been cured or eliminated or
treatment has ceased for other reasons. In some embodiments, the delivery
of one treatment is still occurring when the delivery of the second
begins, so that there is overlap in terms of administration. This is
sometimes referred to herein as "simultaneous" or "concurrent delivery."
In other embodiments, the delivery of one treatment ends before the
delivery of the other treatment begins. In some embodiments of either
case, the overall treatment is more effective because of combined
administration. For example, the L-DOPA treatment is more effective,
e.g., an equivalent effect is seen with less L-DOPA, one or more
deleterious effects associated with L-DOPA therapy are reduced, or the
L-DOPA treatment reduces PD symptoms to a greater extent, than would be
seen if the L-DOPA were administered in the absence of the compounds
disclosed herein. Conversely, the analogous situation can be observed
wherein the compounds of formulae (I)-(XVI) are more effective when
administered in combination with L-DOPA. In some embodiments, delivery is
such that the reduction in a symptom, or other parameter related to the
disorder is greater than what would be observed with one treatment
delivered in the absence of the other. The effect of the two treatments
can be partially additive, wholly additive, or greater than additive
(synergistic).

[0173] The compounds of formulae (I)-(XVI) and L-DOPA, and optionally at
least one additional therapeutic agent can be administered
simultaneously, in the same or in separate compositions, or sequentially.
For sequential administration, either the compounds of formulae (I)-(XVI)
or the L-DOPA can be administered first, or the order of administration
can be reversed. Similarly, any optional additional therapeutic agent(s)
can be administered prior to or after administration of the compounds of
formulae (I)-(XVI) and/or L-DOPA.

[0174] Accordingly, in some embodiments, the methods relate to a method
for treating Parkinson's disease and/or a symptom associated with
Parkinson's disease, wherein the method comprises administration of a
dose-spared amount of L-DOPA, or a composition comprising a dose-spared
amount of L-DOPA. As used herein, "dose-spared" amount of L-DOPA means
that the effective amount of L-DOPA is reduced relative to the effective
amount that would commonly be required to exert the desired beneficial
effect. Thus, in certain embodiments, the disclosure provides for
compositions and formulations that comprise an effective amount of at
least one compound of formulae (I)-(XVI) and a dose-spared amount of
L-DOPA.

[0175] The subject may be a eukaryote, an animal, a vertebrate animal, a
mammal, a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine
(e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a
horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g.
marmoset, baboon), an ape (e.g. gorilla, chimpanzee, orangutan, gibbon),
or a human.

Formulations

[0176] While it is possible for the active compound to be administered
alone, it can be formulated as a pharmaceutical composition (e.g.
formulation) comprising at least one active compound, as defined above,
together with one or more pharmaceutically acceptable carriers,
adjuvants, excipients, diluents, fillers, buffers, stabilizers,
preservatives, lubricants, or other materials well known to those skilled
in the art and optionally other therapeutic or prophylactic agents.

[0177] Thus, the disclosure further provides pharmaceutical compositions,
as defined above, and methods of making a pharmaceutical composition
comprising admixing at least one active compound, as defined above,
together with one or more pharmaceutically acceptable carriers,
excipients, buffers, adjuvants, stabilizers, or other materials, as
described herein.

[0178] The term "pharmaceutically acceptable" as used herein pertains to
compounds, materials, compositions, and/or dosage forms which are, within
the scope of sound medical judgment, suitable for use in contact with the
tissues of a subject (e.g. human) without excessive toxicity, irritation,
allergic response, or other problem or complication, commensurate with a
reasonable benefit/risk ratio. Each carrier, excipient, etc. must also be
"acceptable" in the sense of being compatible with the other ingredients
of the formulation.

[0180] The formulations may conveniently be presented in unit dosage form
and may be prepared by any methods well known in the art of pharmacy.
Such methods include the step of bringing into association the active
compound with the carrier which constitutes one or more accessory
ingredients. In general, the formulations are prepared by uniformly and
intimately bringing into association the active compound with liquid
carriers or finely divided solid carriers or both, and then if necessary
shaping the product.

[0182] Formulations suitable for oral administration (e.g. by ingestion)
may be presented as discrete units such as capsules, cachets or tablets,
each containing a predetermined amount of the active compound; as a
powder or granules; as a solution or suspension in an aqueous or
non-aqueous liquid; or as an oil-in-water liquid emulsion or a
water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.

[0183] A tablet may be made by conventional means, e.g., compression or
moulding, optionally with one or more accessory ingredients. Compressed
tablets may be prepared by compressing in a suitable machine the active
compound in a free-flowing form such as a powder or granules, optionally
mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol,
tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g.
lactose, microcrystalline cellulose, calcium hydrogen phosphate);
lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g.
sodium starch glycolate, cross-linked povidone, cross-linked sodium
carboxymethyl cellulose); surface-active or dispersing or wetting agents
(e.g. sodium lauryl sulfate); and preservatives (e.g. methyl
p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid). Molded tablets
may be made by molding in a suitable machine a mixture of the powdered
compound moistened with an inert liquid diluent. The tablets may
optionally be coated or scored and may be formulated so as to provide
slow or controlled release of the active compound therein using, for
example, hydroxypropylmethyl cellulose in varying proportions to provide
the desired release profile. Tablets may optionally be provided with an
enteric coating, to provide release in parts of the gut other than the
stomach.

[0184] Formulations suitable for topical administration (e.g. transdermal,
intranasal, ocular, buccal, and sublingual) may be formulated as an
ointment, cream, suspension, lotion, powder, solution, past, gel, spray,
aerosol, or oil. Alternatively, a formulation may comprise a patch or a
dressing such as a bandage or adhesive plaster impregnated with active
compounds and optionally one or more excipients or diluents.

[0185] Formulations suitable for topical administration in the mouth
include lozenges comprising the active compound in a flavored basis,
usually sucrose and acacia or tragacanth; pastilles comprising the active
compound in an inert basis such as gelatin and glycerin, or sucrose and
acacia; and mouthwashes comprising the active compound in a suitable
liquid carrier.

[0186] Formulations suitable for topical administration to the eye also
include eye drops wherein the active compound is dissolved or suspended
in a suitable carrier, especially an aqueous solvent for the active
compound.

[0187] Formulations suitable for nasal administration, wherein the carrier
is a solid, include a coarse powder having a particle size, for example,
in the range of about 20 to about 500 microns which is administered in
the manner in which snuff is taken, i.e. by rapid inhalation through the
nasal passage from a container of the powder held close up to the nose.
Suitable formulations wherein the carrier is a liquid for administration
as, for example, nasal spray, nasal drops, or by aerosol administration
by nebulizer, include aqueous or oily solutions of the active compound.

[0188] Formulations suitable for administration by inhalation include
those presented as an aerosol spray from a pressurized pack, with the use
of a suitable propellant, such as dichlorodifluoromethane,
trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or
other suitable gases.

[0189] Formulations suitable for topical administration via the skin
include ointments, creams, and emulsions. When formulated in an ointment,
the active compound may optionally be employed with either a paraffinic
or a water-miscible ointment base. Alternatively, the active compounds
may be formulated in a cream with an oil-in-water cream base. If desired,
the aqueous phase of the cream base may include, for example, at least
about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or
more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol,
sorbitol, glycerol and polyethylene glycol and mixtures thereof. The
topical formulations may desirably include a compound which enhances
absorption or penetration of the active compound through the skin or
other affected areas. Examples of such dermal penetration enhancers
include dimethylsulfoxide and related analogues.

[0190] When formulated as a topical emulsion, the oily phase may
optionally comprise merely an emulsifier (otherwise known as an
emulgent), or it may comprises a mixture of at least one emulsifier with
a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic
emulsifier is included together with a lipophilic emulsifier which acts
as a stabilizer. It is also preferred to include both an oil and a fat.
Together, the emulsifier(s) with or without stabilizer(s) make up the
so-called emulsifying wax, and the wax together with the oil and/or fat
make up the so-called emulsifying ointment base which forms the oily
dispersed phase of the cream formulations.

[0191] Suitable emulgents and emulsion stabilizers include Tween 60, Span
80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and
sodium lauryl sulphate. The choice of suitable oils or fats for the
formulation is based on achieving the desired cosmetic properties, since
the solubility of the active compound in most oils likely to be used in
pharmaceutical emulsion formulations may be very low. Thus the cream
should preferably be a non-greasy, non-staining and washable product with
suitable consistency to avoid leakage from tubes or other containers.
Straight or branched chain, mono- or dibasic alkyl esters such as
diisoadipate, isocetyl stearate, propylene glycol diester of coconut
fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate,
butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain
esters known as Crodamol CAP may be used, the last three being preferred
esters. These may be used alone or in combination depending on the
properties required. Alternatively, high melting point lipids such as
white soft paraffin and/or liquid paraffin or other mineral oils can be
used.

[0192] Formulations suitable for rectal administration may be presented as
a suppository with a suitable base comprising, for example, cocoa butter
or a salicylate.

[0193] Formulations suitable for vaginal administration may be presented
as pessaries, tampons, creams, gels, pastes, foams or spray formulations
containing in addition to the active compound, such carriers as are known
in the art to be appropriate.

[0194] Formulations suitable for parenteral administration (e.g. by
injection, including cutaneous, subcutaneous, intramuscular, intravenous
and intradermal), include aqueous and nonaqueous isotonic, pyrogen-free,
sterile injection solutions which may contain anti-oxidants, buffers,
preservatives, stabilisers, bacteriostats, and solutes which render the
formulation isotonic with the blood of the intended recipient; and
aqueous and non-aqueous sterile suspensions which may include suspending
agents and thickening agents, and liposomes or other microparticulate
systems which are designed to target the compound to blood components or
one or more organs. Examples of suitable isotonic vehicles for use in
such formulations include Sodium Chloride Injection, Ringer's Solution,
or Lactated Ringer's Injection. Typically, the concentration of the
active compound in the solution is from about 1 ng/ml to about 10
μg/ml, for example from about 10 ng/ml to about 1 μg/ml. The
formulations may be presented in unit-dose or multi-dose sealed
containers, for example, ampoules and vials, and may be stored in a
freeze-dried (lyophilised) condition requiring only the addition of the
sterile liquid carrier, for example water for injections, immediately
prior to use. Extemporaneous injection solutions and suspensions may be
prepared from sterile powders, granules, and tablets. Formulations may be
in the form of liposomes or other microparticulate systems which are
designed to target the active compound to blood components or one or more
organs.

[0195] In some embodiments, the disclosure provides a pharmaceutical
composition comprising a compound having the following formula:

##STR00030##

[0196] or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.

Dosages

[0197] It will be appreciated that appropriate dosages of the active
compounds, and compositions comprising the active compounds, can vary
from patient to patient. Determining the optimal dosage will generally
involve the balancing of the level of therapeutic benefit against any
risk or deleterious side effects of the treatments of the present
invention. The selected dosage level will depend on a variety of factors
including, but not limited to, the activity of the particular compound,
the route of administration, the time of administration, the rate of
excretion of the compound, the duration of the treatment, other drugs,
compounds, and/or materials used in combination, and the age, sex,
weight, condition, general health, and prior medical history of the
patient. The amount of compound and route of administration will
ultimately be at the discretion of the physician, although generally the
dosage will be to achieve local concentrations at the site of action
which achieve the desired effect without causing substantial harmful or
deleterious side-effects.

[0198] Administration in vivo can be effected in one dose, continuously or
intermittently (e.g. in divided doses at appropriate intervals)
throughout the course of treatment. Methods of determining the most
effective means and dosage of administration are well known to those of
skill in the art and will vary with the formulation used for therapy, the
purpose of the therapy, the target cell being treated, and the subject
being treated. Single or multiple administrations can be carried out with
the dose level and pattern being selected by the treating physician.

[0199] In general, a suitable dose of the active compound is in the range
of about 100 μg to about 250 mg per kilogram body weight of the
subject per day. Where the active compound is a salt, an ester, prodrug,
or the like, the amount administered is calculated on the basis of the
parent compound and so the actual weight to be used is increased
proportionately.

EXAMPLES

General Considerations

[0200] Unless stated to the contrary, where applicable, the following
conditions apply. Air sensitive reactions were carried out using dried
solvents (see below) and under a slight static pressure of Ar
(pre-purified quality) that had been passed through a column of Drierite.
Glassware was dried in an oven at 120° C. for at least 12 h prior
to use and then assembled quickly while hot, sealed with rubber septa,
and allowed to cool under a stream of Ar. Reactions were stirred
magnetically using Teflon-coated magnetic stirring bars. Teflon-coated
magnetic stirring bars and syringe needles were dried in an oven at
120° C. for at least 12 h prior to use. Commercially available
Norm-Ject disposable syringes were used. All 1H and 13C NMR
spectra were recorded on 300 MHz or 400 MHz Varian Mercury spectrometers
as noted. 1H spectra were referenced to CHCl3 at 7.26 ppm and
13C spectra were referenced to CDCl3 at 77.23 ppm. All spectra
were taken in CDCl3 unless otherwise noted. Thin layer
chromatography (TLC) was carried out on Merck silica gel 60 F254
aluminum backed plates and visualized using 254 nm UV light. Flash
chromatographic purifications were performed using silica gel (40-60
μm) purchased from Agela Technologies (Newark, Del.). Compounds and
solvents were obtained from Fisher, Sigma-Aldrich, and VWR and used
without further purification unless noted below.

Example 1

Synthesis of Ethers

[0201] The following example is representative for the formation of all
diaryl ethers from their respective phenols or thiophenols and
para-bromobenzaldehyde.

[0215] The following example is representative for the formation of all
methyl esters from their respective cinnamic acids with TMSCHN2.

##STR00043##

[0216] (E)-methyl 3-(4-trifluoromethyl)phenyl)acrylate: A solution of
TMSCHN2 (2.0 M in hexanes, 1.6 eq) was added dropwise with stirring
to a 0° C. solution of the
(E)-3-(4-(trifluoromethyl)phenyl)acrylic acid (0.25 M) in
benzene:methanol (2:1). The reaction was allowed to warm to rt over the
course of 0.5 h. Concentration of the reaction mixture afforded the
desired (E)-methyl 3-(4-trifluoromethyl)phenyl)acrylate as a white solid
in 99% yield (0.898 g).

[0221] The following example is representative for the formation of all
trans-alkenes from the corresponding benzaldehyde and methyl
diethylphosphonoacetate through a Horner-Wadsworth-Emmons olefination.

[0271] The following example is representative for Curtius rearrangement
of carboxylic acids to general the corresponding t-butylcarbamate
protected amines using diphenylphosphorylazide, triethylamine and
t-butanol. In some cases, the carbamate could not be purified completely
so impure material was taken on to the subsequent hydrolysis step.

[0300] Locomotor activity of DAT-KO mice were measured in an Omnitech
CCDigiscan (Accuscan Instruments, Columbus, Ohio) activity monitor under
bright illumination (Gainetdinov et al. Science, 1999, 283, p. 397-401).
All behavioral experiments were performed between 10:00 am and 5:00 pm.
Activity was measured at 5 min intervals. To evaluate the effects of the
treatments on motor behaviors, the mice were placed into activity monitor
chambers (20×20 cm) for 30 min and then treated with α-MT
(250 mg/kg, i.p.). The compound were injected 1 h after α-MT
administration and various parameters of locomotor activity were
monitored for up to 3 h. In cumulative dosing experiments, animals were
treated with increasing doses of drugs at 1 h intervals.

[0301] Results are illustrated in FIGS. 1-6. After administration of the
compounds alone, the overall movement of the mice was observed and
recorded. As seen in FIG. 1, the experiment with compound 2 was not
completed because it was lethal after 30 mg/kg. Similarly, compound 6
caused seizures and paralysis in the mice after 30 mg/kg treatment.
However, compounds 1, 3, 4, 5, and 7 resulted in active mice and reduced
rigidity. The movement included shaking, tail straub, head bobbing and
sniffing, similar to (+)-MDMA treatment. These compounds exhibited marked
anti-akinesia activity. Compound 9, alone, was able to induce normal
locomotion in DDD mice, making it the most promising derivative examined
(FIG. 2). A summary of the overall movement is presented in FIG. 3.

[0302] Several compounds (3, 4, 5, and 7) were also synergistic with
L-DOPA/Carbiodopa treatment (FIG. 4). These compounds enhanced the low
concentration of L-DOPA effects and induced locomotion and vertical
activity. Compound 9 was tested collectively with L-DOPA/Benserazide and
the mice had increased locomotion and vertical activity (FIG. 5). The
results from treatment with the compounds and L-DOPA are summarized in
FIG. 6. This indicates that the compounds may have utility in
dose-sparing L-DOPA, in turn preventing dyskinesias.

[0303] Data are presented as mean±SEM and analyzed using a two-tailed
Student's t-test and one way analysis of variance (ANOVA).

[0306] The forelimb adjusting step task measures the ability of the rat to
adjust to body position shifts imposed by the experimenter and is the rat
homolog of the akinesia seen in PD (Olsson et al. (1995) J Neurosci
15:3863-3875). Rats, held by the experimenter with one unrestrained paw
touching a platform, will be moved in an abduction and adduction
direction (0.9 m/5 sec), and the adjusting steps made by the unrestrained
paw counted. Three stepping trials will be taken per session, and the
average score used. Assessments will be made prior to the 6-OHDA
treatment surgery (i.e., baseline performance), and immediate before and
after each treatment with the compounds.

[0307] Dyskinesia Assessments.

[0308] Animals will be placed in clear Perspex boxes (22 cm×34
cm×20 cm) and allowed 30 min to habituate to the environment.
L-DOPA methyl ester (6 mg/kg, i.p.) will be administered at 20 min time
intervals. Each rat will be observed for 1 min every 20 min for 3 hr. A
scoring system for the three subtypes of abnormal involuntary movements
(AIMs) will be assessed.

[0310] We will assess the anti-Parkinsonian efficacy of test compounds.
Rats treated with 6-OHDA will be assigned a treatment groups: (i)
compound of interest, (ii) LD/CD (positive control; tested at an
efficacious dose) and (iii) vehicle (negative control) (n=12/group; no
shams are needed for this evaluation). Initial doses for test compounds
will be approximately 1/10th of the efficacious dose observed in DDD mice
(approximately 6 mg/kg) and the PD-like rats will be rated for
improvement in forelimb stepping, and the appearance of dyskinesias. In
DDD mice the maximal effects with test compounds were observed
approximately 30 min after dosing; thus for the rats motor deficits and
dyskinesias will be monitored 30, 60, 90 and 120 min after dosing to
capture the maximal efficacy window. In rats, the rating interval will be
based on the Cmax determined from the literature for tranylcypromine
(Sherry et al. (2000) J Affective Disorders 61: 23-29). Tests will be
conducted once a day for five consecutive days (Monday-Friday) at a given
dosage level. Doses will then be increased by approximately 1/2 log order
each week for up to 5 weeks. The highest dose of test compound that
reduces forelimb stepping that had acceptable adverse effects will serve
as a benchmark for subsequent studies.

Example 12

Evaluation of Compounds for Drug Abuse Liability

[0311] Motor deficit improvements resulting from treatments with test
compounds will be determined in the same rats used to evaluate abuse
liability. Three doses (with maximal dose selected from 2.4.2 outcomes)
and saline each will be tested in both PD-like and sham control rats for
both studies. One study will evaluate the abuse liability of compounds
using condition place preference and motor sensitization. Another study
will use intracranial self-stimulation. Extensive research over several
decades has established the validity of each of these assays for
predicting an important component of abuse liability. Together, they
provide a framework for informed regulatory and medical decision making
regarding the abuse potential of compounds.

[0312] Condition Place Preference (CPP) refers to the capacity of a
conditioned stimulus (e.g., environmental context) to acquire the
salience of an unconditioned stimulus (e.g., a drug reward). Thus, CPP
manifests reward-mediated associative learning as demonstrated by the
rats' tendency to spend more time in the environmental context that was
previously paired with the drug reward. CPP expression is thought to
reflect aspects of drug seeking Rats with 6-OHDA-induced lesions within
the striatum can acquire and express methamphetamine-induced CPP (Napier
et al. Movement Disorders 25(7):S283, 2010.); this demonstrates the
utility of this task to ascertain abuse liability in PD-like rats. The D3
receptor preferring agonist, pramipexole, in doses that reversed
6-OHDA-induced motor deficits (i.e., the severe reductions in the
forelimb adjusting task) were sufficient to induce place preference and
motor sensitization in these same rats (Id.). The same protocol can be
used with arylcyclopropylamine compounds.

[0313] Per prior publications (e.g., Dallimore et al. (2006) Behav
Neurosci 120:1103-1114; Shen et al. (2006) J Neurosci 26:11041-11051;
Herrold et al. (2009) Drug Alcohol Depend 99:231-239; Herrold et al.
(2011) Synapse 65:1333-4343; Voigt et al. (2011) Behav Neurosci
125:261-267; Voigt et al. (2011) Behav Brain Res 216:419-423; Voigt et
al. (2011) Behav Brain Res 225:91-96), CPP testing will be done in a
rodent activity apparatus (AccuScan Instruments, Inc., Columbus, Ohio)
(63 cm×30 cm×30 cm) that consists of two larger end chambers
(25 cm) separated by a small center chamber (13 cm). Each chamber has
distinct but neutral visual and tactile cues. Motor activity and time
spent in each chamber will be recorded via 24 photobeams. The CPP task
consists of three phases: pretest, conditioning, and post-test. For the
pretest, rats will be placed into the center chamber, and allowed access
to the entire apparatus for 3 min. Time spent in each context will be
recorded. The activity box configurations do not impose an inherit bias
for the group, but individual rats show slight side deviations; thus,
these data will be used to assign treatment groups such that the pretest
time spent in each chamber is approximately equal across the all
conditioning treatment groups. Conditioning procedures, initiated two
days later, will consist of treating the rats and immediately placing
them in the assigned side for 45 min. Treatment pairings will be
alternated with saline; e.g., drug conditioning may occur on days 1, 3, 5
and 7, and with the saline vehicle on days 2, 4, 6 and 8 rats.
Saline-conditioned rats will receive saline on all 8 days. One day after
the last conditioning session, rats will be given a post-test using the
same procedures described for the pretest. Time spent in the drug-paired
chamber will be compared for the pretest and post-test to determine
whether shifts in chamber preference occurred as a consequence of
conditioning. Place preference is revealed by an increase in time spent
in the drug-paired chamber during the post-test compared to the same
chamber during the pretest.

[0314] Motor Sensitization.

[0315] Repeated intermittent administration of abused psychoactive drugs
(e.g., amphetamine, MDMA, etc.) in rodents causes a progressive increase
in drug-induced motor activity that is higher in magnitude compared to
that induced by a single injection. Motor sensitization reflects neuronal
adaptations that recapitulate aspects of those seen in addicted humans.
Thus, the emergence of motor sensitization in rodents treated with a
novel compound indicates potential abuse liability of the compound. The
condition place preference protocol allows simultaneous assessment of
motor sensitization (Shen et al. (2006) Neurosci 26:11041-11051). To do
so, motor activity will be monitored throughout the 45 min conditioning
periods, and sensitization is verified by a within subjects comparisons
of the first and last treatment.

[0316] Intracranial Self Stimulation.

[0317] ICSS experiments will be conducted in operant chambers
(Med-Associates, St. Albans, Vt.) outfitted with a chamber light, and two
retractable levers each under a stimulus light. Electrical brain
stimulation (EBS) will be delivered by a programmable stimulator via
bipolar leads connected to commutators mounted above the chamber. As has
been published (Rokosik et al. (2011) J Neurosci Methods 198:260-269) and
shown to be effective in rat models of PD (Rokosik et al. (2010) Movement
Disorder s25(7):5285), the rats will be trained to press a lever using a
standardized EBS (200 μs biphasic square wave pulses, applied at 100
Hz for 500 ms). The initial current intensity (100 μA) will be
adjusted for each rat until stable ICSS is reached in a fixed ratio-1
(FR-1) reinforcement schedule for a 30 min session. Rats then will be
pseudo-randomly presented with one of 16 different current frequencies
tested in 10 Hz increments, ranging from 10-160 Hz. For each frequency,
rats will have access to the lever for 2 min and lever presses will be
recorded. The lever then will be retracted for 10 sec. In each session, a
lever pressing rate vs. ICSS current frequency (i.e., Rate-Frequency
Function) will be collected and the maximal (Emax) number of lever
presses determined using a non-linear regression. Once stable, an average
of three curves will used to determine ICSS frequencies that produced
90%, 60% and 10% of Emax (termed `effective current` (ECur); ECur90,
ECur60 and ECur10, respectively. A reduction in the ECur60
or an increase in the ECur10 during treatment with a compound would
indicate an enhancement in ICSS-mediated reward and thus indicate an
abuse liability.

[0318] Alternative approaches can be implemented should a compound or a
dose show abuse potential in one of the planned tasks but not the others,
with the idea that converging evidence from a large set of more diverse
tasks would be useful in this instance. Moreover, this aids in
establishing the breadth of conditions under which a compound may be
abused. For example, rats can be trained to self-administer cocaine (or
another drug of abuse) by lever pressing in an operant box similar to
that used for ICSS. Once rats exhibit stable drug intake, the training
drug can be substituted by an experimental compound. If the experimental
drug is self-administered this indicates potential drug abuse liability.
In such a case, drug-naive rats can then be tested to assess whether the
compound is self-administered in subjects that have no prior drug
experience, providing stronger evidence for the abuse liability of the
novel compound. Drug discrimination protocols could be implemented. In
this task, rats are trained to discriminate between a drug of abuse
(e.g., cocaine and MDMA) and vehicle in a two-lever food-reinforced
procedure. Following training, rats are tested with an experimental drug
to determine whether generalization (`substitution`) to the drug of abuse
cue occurs, indicative of potential abuse liability and a shared
pharmacological target. Alternatively, rats could be trained to
discriminate between an experimental compound and vehicle, and
substitution tests with various drugs of abuse (MDMA, cocaine,
amphetamine, etc.) could be run for generalization.

Example 13

Assessment of L-DOPA Dose-Sparing and Anti-Dyskinesia Activities

[0319] Studies will also ascertain the capacity of the compounds to
enhance the motoric efficacy of LDOPA in lesioned rats. 6-OHDA-treated
rats will be assigned to one of four treatment groups (n=12/group). Rats
in Group B and C will receive either a dose of the test compounds that is
less than the minimal efficacious dose observed in earlier studies.

[0320] In addition to the test compounds, rats will be given an ascending
dose regimen of LD/CD. A comparator group will be treated with test
compound vehicle plus the same ascending dose regimen of LD/CD. The dose
of test compound administered to Group B (*) will be either (a) a dose at
less than the minimum efficacious dose (based on stepping deficit
assessments), or (b) the maximally tolerated dose (based on dyskinesia
assessments) observed in Study 1. LD/CD doses of less than 8/2 mg/kg are
not expected to exhibit anti-Parkinsonian or pro-dyskinetic effects in
rats. Thus, these experiments are designed to determine if the test
compounds enhance the effects of sub-therapeutic doses of LD/CD. L-DOPA
sparing activity will be identified by enhanced efficacy on improving
stepping deficits with sub-therapeutic doses of L-DOPA. The dosing of
test compound and LD/CD will be done so that Cmax and maximal therapeutic
effect for both LD and the test compound occurs within the same time
frame. Cmax will be determined experimentally, but it is of note that
previous PK data are available for tranylcypromine (Sherry, 2000), and
thus may serve as a starting point for these studies.

[0321] The results of these studies should demonstrate whether or not the
administration of test compounds at low efficacious or sub-efficacious
doses will produce enhance efficacy of LD/CD. Importantly, these studies
will also test whether or not the combination of either of the two test
compounds with LD/CD alters the pro-dyskinetic and/or anti-Parkinsonian
effects of LD. Dyskinesias are consistently observed in animals given
LD/CD at 8/2 mg/kg so it should be possible to compare the effects of
LD/CD alone at this dose with the combined effects of LD/CD and the test
compound.

Example 14

Evaluation of Compounds in MPTP-Lesioned Monkey Models of PD

[0322] Squirrel monkeys made Parkinsonian by injections of MPTP will be
used. Animals will be drawn from a cohort of MPTP-lesioned animals that
have shown stable Parkinsonism scores over a period of more than 8
months. Animals will be rated according to standardized rating scales by
two independent raters, blinded to the treatment.

[0323] The efficacy of test compounds will be assessed. Four groups of
animals (n=5-6/group) matched for gender and Parkinsonian disability will
be dosed with either vehicle (Group A), increasing doses of test
compounds (Groups B & C) or an efficacious dose of LD/CD (8/2 mg/kg,
Group D). Baseline ratings for animals are obtained on Mondays and
animals are dosed on Tuesday-Friday and rated daily. Initial doses for
test compounds will be approximately 1/10th of the efficacious dose
observed in DDD mice (approximately 6 mg/kg) and animals will be rated
for improvement in PD scores, the appearance of dyskinesias and closely
monitored for other adverse effects. In DDD mice the maximal effects with
test compounds were observed approximately 30 minutes after dosing. In
monkeys, the rating interval will be based on the Cmax determined from
the literature for tranylcypromine. Animals will be rated for
Parkinsonism and dyskinesias at additional intervals around the Cmax
(e.g. 30, 60, 90 and 120 minutes after dosing) in order to capture the
maximal efficacy window. Animals will be dosed for up to four consecutive
days (Tuesday-Friday) at a given dosage level. Doses will then be
increased by approximately 1/2 log order each week for up to 5 weeks. The
lowest dose of test compound that produces reductions in Parkinsonism
will be used as a benchmark for the next phase of the studies (see
below). If no dose is found that reduces Parkinsonism than the highest
dose that had acceptable adverse effects will be used. Select plasma
levels will be drawn and concentrations of test compounds assayed to
establish basic PK parameters (Cmax and exposure) for these compounds to
guide efficacy evaluations.

[0324] Animals from the above studies will be "washed out" for two weeks
with continued daily ratings for Parkinsonism and dyskinesia. Based on
our previous experience, LD/CD treated animals will return to their
pre-treatment baseline values during this period. After washout, animals
in Group B and C will receive either a dose that is less than the minimal
efficacious dose observed in the above experiment or if no
anti-Parkinsonian efficacy is observed, the maximally tolerated dose. In
addition to the test compound, animals will be given an ascending dose
regimen of LD/CD. A comparator group (Group D) will be treated with
vehicle plus the same ascending dose regimen of LD/CD.

[0325] The dose of test compound administered to Group B (*) will be
either (a) a dose at less than the minimum efficacious dose or (b) the
maximally tolerated dose observed in the Phase 1 study. In our experience
LD/CD doses of less than 8/2 mg/kg do not result in anti-Parkinsonian or
pro-dyskinetic effects in monkeys. Thus, these experiments are designed
to determine if the test compounds enhance the effects of sub-therapeutic
doses of LD/CD. L-DOPA sparing activity will be identified by enhanced
efficacy with sub-therapeutic doses of L-DOPA. The dosing of test
compound and LD/CD will be done so that Cmax and maximal therapeutic
effect for both LD and the test compound occurs within the same time
frame. Relative dosing intervals will be based on PK values obtained in
these animals. The results of these studies should demonstrate whether or
not the administration of test compounds at low efficacious or
subefficacious doses will produce enhance efficacy of LD/CD. Importantly,
these studies will also test whether or not the combination of either of
the 2 test compounds with LD/CD enhances the pro-dyskinetic as well as
anti-Parkinsonian effects of LD. Finally, the results of these studies
could point to an anti-dyskinetic effect for the compound. We
consistently observe dyskinesias in animals given LD/CD at 8/2 mg/kg so
it will be possible to compare the effects of LD/CD alone at this dose
with the combined effects of LD/CD and the test compound.

[0326] Although the disclosure above has been described in terms of
various aspects and specific embodiments, it is not so limited. A variety
of suitable alterations and modifications for operation under specific
conditions will be apparent to those skilled in the art. It is therefore
intended that the following claims be interpreted as covering all such
alterations and modifications as fall within the spirit and scope of the
invention.

[0327] All patents, publications and references cited herein are hereby
fully incorporated by reference. In case of conflict between the present
disclosure and incorporated patents, publications and references, the
present disclosure should control.